Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): National Research, Development and Innovation Fund of Hungary; Ministry of Human Capacities of Hungary Introduction Myocardial sodium-glucose cotransporter 1 (SGLT1) has been shown to contribute to cardiac pathological processes, whereas humans with functionally limited SGLT1 are at lower risk of developing heart failure (HF). The novel HF medications, SGLT2 inhibitors, non-selectively inhibit SGLT1 to different extent, therefore, characterization of its expression in disease conditions is relevant. Purpose To investigate left ventricular (LV) SGLT1 expression in humans with end-stage HF, and in a rat model of HF. Methods Myocardial LV samples were harvested from control subjects (Controls, n=9) undergoing valve surgery, and from patients with end-stage dilated cardiomyopathy (DCM, n=12) undergoing heart transplantation. The rat model of aorto-caval fistula (ACF, n=12) was used to induce HF with predominant LV dilation in rats during a course of 24 weeks; sham-operated animals served as controls (Sham-A, n=12). Echocardiography was used to assess LV structure and function prior to surgery in humans, as well as in rats at the end of the follow-up period. Western blotting was performed to characterize LV SGLT1 protein expression and to investigate the activity of the master regulators AMPK and ERK1/2. The extent of LV nitro-oxidative stress was quantified by immunohistochemistry (3-nitrotyrosine) in rats with HF. Results Both humans with DCM and rats with ACF-induced HF presented with severely dilated LVs compared to respective controls, whereas LV SGLT1 protein expression was significantly upregulated similarly by ~1.7-fold in both cases (both P<0.01). These increases in SGLT1 expressions were accompanied by significant reductions in ERK1/2 activating phosphorylation (both P<0.05), whereas AMPK activity was unaffected. In rats with HF, LV SGLT1 expression correlated significantly with the extent of myocardial nitro-oxidative stress (r=0.762, P=0.037). Conclusions LV SGLT1 expression is upregulated in HF in both humans and small animals, and ERK1/2 shows a concomitantly reduced activity. LV SGLT1 expression correlates with the extent of nitro-oxidative stress, suggesting a possible pathological role in HF. Whether SGLT2 inhibitors exert direct cardiac actions via inhibition of myocardial SGLT1 needs to be elucidated.

中文翻译：

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左心室 SGLT1 表达在人和大鼠模型的心力衰竭中上调

资金致谢 资金来源类型：公共拨款——仅限国家预算。主要资金来源：匈牙利国家研究、发展和创新基金；匈牙利人力资源部 简介 心肌钠-葡萄糖协同转运蛋白 1 (SGLT1) 已被证明有助于心脏病理过程，而 SGLT1 功能受限的人发生心力衰竭 (HF) 的风险较低。新型 HF 药物 SGLT2 抑制剂在不同程度上非选择性地抑制 SGLT1，因此，对其在疾病条件下表达的表征是相关的。目的 研究人类终末期心衰和心衰大鼠模型中左心室 (LV) SGLT1 的表达。方法 从接受瓣膜手术的对照受试者（对照，n = 9）中采集心肌 LV 样本，以及接受心脏移植的终末期扩张型心肌病（DCM，n=12）患者。大鼠主动脉腔静脉瘘模型（ACF，n=12）用于在 24 周的过程中在大鼠中诱导 HF，主要是 LV 扩张；假手术动物作为对照（Sham-A，n = 12）。超声心动图用于评估人类手术前的 LV 结构和功能，以及随访期结束时的大鼠。进行蛋白质印迹以表征 LV SGLT1 蛋白表达并研究主调节剂 AMPK 和 ERK1/2 的活性。LV 硝基氧化应激的程度通过免疫组织化学（3-硝基酪氨酸）在 HF 大鼠中进行量化。结果 与各自的对照相比，患有 DCM 的人和患有 ACF 诱导的 HF 的大鼠都呈现出严重扩张的 LV，而 LV SGLT1 蛋白表达在两种情况下同样显着上调约 1.7 倍（均 P < 0.01）。SGLT1 表达的这些增加伴随着 ERK1/2 激活磷酸化的显着降低（均 P < 0.05），而 AMPK 活性不受影响。在心衰大鼠中，LV SGLT1 表达与心肌硝基氧化应激程度显着相关（r=0.762，P=0.037）。结论 LV SGLT1 在人类和小动物的 HF 中表达上调，ERK1/2 的活性随之降低。LV SGLT1 表达与硝基氧化应激的程度相关，表明在 HF 中可能具有病理作用。需要阐明 SGLT2 抑制剂是否通过抑制心肌 SGLT1 发挥直接心脏作用。